Whole exome sequencing identifies frequent somatic mutations in cell-cell adhesion genes in chinese patients with lung squamous cell carcinoma

Lung squamous cell carcinoma (SQCC) accounts for about 30% of all lung cancer cases. Understanding of mutational landscape for this subtype of lung cancer in Chinese patients is currently limited. We performed whole exome sequencing in samples from 100 patients with lung SQCCs to search for somatic mutations and the subsequent target capture sequencing in another 98 samples for validation. We identified 20 significantly mutated genes, including TP53, CDH10, NFE2L2 and PTEN. Pathways with frequently mutated genes included those of cell-cell adhesion/Wnt/Hippo in 76%, oxidative stress response in 21%, and phosphatidylinositol-3-OH kinase in 36% of the tested tumor samples. Mutations of Chromatin regulatory factor genes were identified at a lower frequency. In functional assays, we observed that knockdown of CDH10 promoted cell proliferation, soft-agar colony formation, cell migration and cell invasion, and overexpression of CDH10 inhibited cell proliferation. This mutational landscape of lung SQCC in Chinese patients improves our current understanding of lung carcinogenesis, early diagnosis and personalized therapy

Promises and challenges of adoptive T-cell therapies for solid tumours

From Springer Nature via Jisc Publications RouterHistory: received 2020-11-09, rev-recd 2021-02-22, accepted 2021-03-04, registration 2021-03-04, pub-electronic 2021-03-29, online 2021-03-29, pub-print 2021-05-25Publication status: PublishedFunder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272; Grant(s): RCF18/046Funder: Ovarian Cancer Action; doi: https://doi.org/10.13039/501100000299; Grant(s): HER000762Abstract: Cancer is a leading cause of death worldwide and, despite new targeted therapies and immunotherapies, many patients with advanced-stage- or high-risk cancers still die, owing to metastatic disease. Adoptive T-cell therapy, involving the autologous or allogeneic transplant of tumour-infiltrating lymphocytes or genetically modified T cells expressing novel T-cell receptors or chimeric antigen receptors, has shown promise in the treatment of cancer patients, leading to durable responses and, in some cases, cure. Technological advances in genomics, computational biology, immunology and cell manufacturing have brought the aspiration of individualised therapies for cancer patients closer to reality. This new era of cell-based individualised therapeutics challenges the traditional standards of therapeutic interventions and provides opportunities for a paradigm shift in our approach to cancer therapy. Invited speakers at a 2020 symposium discussed three areas—cancer genomics, cancer immunology and cell-therapy manufacturing—that are essential to the effective translation of T-cell therapies in the treatment of solid malignancies. Key advances have been made in understanding genetic intratumour heterogeneity, and strategies to accurately identify neoantigens, overcome T-cell exhaustion and circumvent tumour immunosuppression after cell-therapy infusion are being developed. Advances are being made in cell-manufacturing approaches that have the potential to establish cell-therapies as credible therapeutic options. T-cell therapies face many challenges but hold great promise for improving clinical outcomes for patients with solid tumours

Promises and challenges of adoptive T-cell therapies for solid tumours.

Cancer is a leading cause of death worldwide and, despite new targeted therapies and immunotherapies, many patients with advanced-stage- or high-risk cancers still die, owing to metastatic disease. Adoptive T-cell therapy, involving the autologous or allogeneic transplant of tumour-infiltrating lymphocytes or genetically modified T cells expressing novel T-cell receptors or chimeric antigen receptors, has shown promise in the treatment of cancer patients, leading to durable responses and, in some cases, cure. Technological advances in genomics, computational biology, immunology and cell manufacturing have brought the aspiration of individualised therapies for cancer patients closer to reality. This new era of cell-based individualised therapeutics challenges the traditional standards of therapeutic interventions and provides opportunities for a paradigm shift in our approach to cancer therapy. Invited speakers at a 2020 symposium discussed three areas-cancer genomics, cancer immunology and cell-therapy manufacturing-that are essential to the effective translation of T-cell therapies in the treatment of solid malignancies. Key advances have been made in understanding genetic intratumour heterogeneity, and strategies to accurately identify neoantigens, overcome T-cell exhaustion and circumvent tumour immunosuppression after cell-therapy infusion are being developed. Advances are being made in cell-manufacturing approaches that have the potential to establish cell-therapies as credible therapeutic options. T-cell therapies face many challenges but hold great promise for improving clinical outcomes for patients with solid tumours

Aerosol Optical Depth over the Arctic Snow-Covered Regions Derived from Dual-Viewing Satellite Observations

Aerosol properties over the Arctic snow-covered regions are sparsely provided by temporal and spatially limited in situ measurements or active Lidar observations. This introduces large uncertainties for the understanding of aerosol effects on Arctic climate change. In this paper, aerosol optical depth (AOD) is derived using the advanced along-track scanning radiometer (AATSR) instrument. The basic idea is to utilize the dual-viewing observation capability of AATSR to reduce the impacts of AOD uncertainties introduced by the absolute wavelength-dependent error on surface reflectance estimation. AOD is derived assuming that the satellite observed surface reflectance ratio can be well characterized by a snow bidirectional reflectance distribution function (BRDF) model with a certain correction direct from satellite top of the atmosphere (TOA) observation. The aerosol types include an Arctic haze aerosol obtained from campaign measurement and Arctic background aerosol (maritime aerosol) types. The proper aerosol type is selected during the iteration step based on the minimization residual. The algorithm has been used over Spitsbergen for the spring period (April–May) and the AOD spatial distribution indicates that the retrieval AOD can capture the Arctic haze event. The comparison with AERONET observations shows promising results, with a correlation coefficient R = 0.70. The time series analysis shows no systematical biases between AATSR retrieved AOD and AERONET observed ones

Can 9q34.2 rs633862 polymorphism predict survival in epithelial ovarian cancer?

Objective Our previous genome-wide association study (GWAS) identified that the ABO rs633862 variant in chromosome 9q34.2 was associated with the risk of epithelial ovarian cancer (EOC) in Chinese Han women. The aim of the present study was to evaluate its prognostic effect on EOC. Methods A total of 669 EOC patients were enrolled for the genotyping of rs633862 variant in 9q34.2. We used Kaplan–Meier survival curves, univariate and multivariate Cox proportional hazard models to evaluate the association of rs633862 with overall survival (OS) in EOC patients. Results We found that rs633862 variant AG/GG genotypes were significantly associated with a longer OS by using univariate Cox proportional hazards regression analysis, compared with the rs633862 AA genotype (HR = 0.69, 95% CI [0.49–0.98], p = 0.035), albeit with a boardline significance in the multivariate analysis. Similar findings were observed in the subgroup of high-grade serous ovarian carcinoma. Further expression quantitative trait loci (eQTL) analysis indicated that the rs633862 AA genotype was associated with an increased level of ABO mRNA expression (p = 1.8 × 10−11). Conclusions Supplementary to the previous GWAS, our study provides additional evidence on the prognostic value of the 9q34.2 rs633862 variant in EOC patients, and this variant may function by regulating the ABO mRNA expression

<i>REV3L</i>, a Promising Target in Regulating the Chemosensitivity of Cervical Cancer Cells

<div><p>REV3L, the catalytic subunit of DNA Polymerase ζ (Polζ), plays a significant role in the DNA damage tolerance mechanism of translesion synthesis (TLS). The role of <i>REV3L</i> in chemosensitivity of cervical cancer needs exploration. In the present study, we evaluated the expression of the Polζ protein in paraffin-embedded tissues using immunohistochemistry and found that the expression of Polζ in cervical cancer tissues was higher than that in normal tissues. We then established some cervical cancer cell lines with <i>REV3L</i> suppression or overexpression. Depletion of <i>REV3L</i> suppresses cell proliferation and colony formation of cervical cancer cells through G₁ arrest, and <i>REV3L</i> promotes cell proliferation and colony formation of cervical cancer cells by promoting G₁ phase to S phase transition. The suppression of <i>REV3L</i> expression enhanced the sensitivity of cervical cancer cells to cisplatin, and the overexpression of <i>REV3L</i> conferred resistance to cisplatin as evidenced by the alteration of apoptosis rates, and significantly expression level changes of anti-apoptotic proteins B-cell lymphoma 2 (Bcl-2), myeloid cell leukemia sequence 1 (Mcl-1) and B-cell lymphoma-extra large (Bcl-xl) and proapoptotic Bcl-2-associated x protein (Bax). Our data suggest that <i>REV3L</i> plays an important role in regulating cervical cancer cellular response to cisplatin, and thus targeting <i>REV3L</i> may be a promising way to alter chemosensitivity in cervical cancer patients.</p></div

Polζ expression in cervical cancer specimens and normal cervical tissues and mRNA expression of <i>REV3L</i> in cervical cancer cell lines.

<p>(A) Polζ-positive (upper, left panel) and Polζ-negative (upper, right panel) expression in cervical cancer specimens, Polζ-positive (lower, left panel) and Polζ-negative (lower, right panel) expression in normal cervical tissues. (B) The clinical characteristics and the status of Polζ expression of cervical cancer patients and patients with nomal cervix. The mean Polζ expression was higher in the cervical cancer tissues than that in the normal cervical tissues. (C)Real time PCR analysis for <i>REV3L</i> mRNA expression in four cervical cancer cell lines. <i>REV3L</i> expression was higher in HeLa and SiHa cells than in MS751 and ME180 cells. (D) Reverse transcription PCR analysis for <i>REV3L</i> mRNA expression in short hairpin RNA transfected negative control cells (shGFP), shREV3L cells, <i>REV3L</i>-overexpressing cells, and vector control cells. <i>REV3L</i> expression was significantly decreased in shREV3L cells and was increased in the <i>REV3L</i>-overexpressing cells compared with control cells.</p

Influence of upregulation or downregulation of <i>REV3L</i> on cell proliferation, cell cycle, and colony formation ability.

<p>(A) Depletion of <i>REV3L</i> suppressed cell proliferation of HeLa shREV3L cells and SiHa shREV3L cells. (B) Enhancement of <i>REV3L</i> promoted cell proliferation of MS751 <i>REV3L</i> and ME180 <i>REV3L</i> cells. (C) Depletion of <i>REV3L</i> induced G₁ arrest in HeLa shREV3L cells. (D) Enhancement of <i>REV3L</i> promoted G₁ phase to S phase transition in ME180 <i>REV3L</i> cells. (E) Depletion of <i>REV3L</i> suppressed colony formation of HeLa shREV3L and SiHa shREV3L cells. (F) Enhancement of <i>REV3L</i> promoted colony formation of MS751 <i>REV3L</i> and ME180 <i>REV3L</i> cells. Data are means of three independent experiments ± SEM. * <i>P</i>< 0.05.</p